on March 2, 2006
Published online before print March 2, 2006, doi: 10.1161/01.ATV.0000215951.36219.a4
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Submitted on February 5, 2006
Accepted on February 10, 2006
Endothelial Dysfunction and Low-Grade Inflammation Explain Much of the Excess Cardiovascular Mortality in Individuals With Type 2 Diabetes. The Hoorn Study
Jolien de Jager ;
From the Department of Internal Medicine, Bethesda General Hospital, Hoogeveen, the Netherlands (J.d.J., A.K); the Institute for Research in Extramural Medicine (J.M.D., P.J.K., G.N., R.J.H., L.M.B., C.D.A.S.), VU University Medical Center, Amsterdam, The Netherlands; and the Department of Internal Medicine, University Hospital Maastricht, The Netherlands (C.D.A.S.).
* To whom correspondence should be addressed. E-mail: csteh{at}sint.azm.nl.
Objective--The mechanisms responsible for the increased cardiovascular disease risk that accompanies type 2 diabetes (T2D) remain poorly understood. It is commonly held that endothelial dysfunction and low-grade inflammation can explain, at least in part, why deteriorating glucose tolerance is associated with cardiovascular disease. However, there is no direct evidence for this contention.
Methods and Results--In this population-based study (n=631), T2D was cross-sectionally associated with both endothelial dysfunction and low-grade inflammation, whereas impaired glucose metabolism (IGM) was associated only with low-grade inflammation. These findings were independent of other risk factors that accompany T2D or IGM. During a follow-up of 11.7 years (median; range 0.5 to 13.2 years), low-grade inflammation was associated with a greater risk of cardiovascular mortality (hazard ratio, 1.43 [95% CI, 1.17 to 1.77] per 1 SD difference). For endothelial dysfunction, the association with cardiovascular mortality was stronger in diabetic (hazard ratio, 1.87 [95% CI, 1.43 to 2.45]) than in nondiabetic individuals (hazard ratio, 1.23 [95% CI, 0.86 to 1.75]; P interaction=0.06). Finally, T2D-associated endothelial dysfunction and low-grade inflammation explained 
43% of the increase in cardiovascular mortality risk conferred by T2D.
Conclusions--These data emphasize the necessity of randomized controlled trials of strategies that aim to decrease cardiovascular disease risk by improving endothelial function and decreasing low-grade inflammation, especially for T2D patients.
Key words: epidemiology • diabetes mellitus • endothelium • inflammation • mortality
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